This application proposes the continuation of our program of clinical and basic neuropharmacological research to explore the biochemical pathophysiology of affective disorders and the mechanisms of action of drugs used in their treatment. The long-term objective of this research is the development of a clinically and therapeutically relevant classification of depressive disorders based on differences in the biochemical pathophysiology of different types of depressions. In our recent studies we have tentatively identified three biochemically discrete groups of depressive disorders, on the basis of differences in catecholamine metabolites and platelet monoamine oxidase activity. The research proposed in this grant application will attempt to confirm and extend these findings and to explore their pathophysiological and therapeutic implications. In addition to examining catecholamine metabolites and related enzymes, we shall explore other biochemical criteria such as platelet serotonin uptake and plasma and urinary cortisol that may define additional clinically and therapeutically relevant groupings of depressive disorders. The use of biochemical criteria as predictors of response to specific forms of antidepressant pharmacotherapy will be studied in this project. In correlative basic research that includes studies of thresholds of intracranial reinforcement in animals, we shall explore two recently described behavioral paradigms that may provide animal models of two of three biochemically characterized groups of depressive disorders that we have tentatively identified in our recent clinical investigations.